Background: After 30 years of the HIV epidemic, in the past few months, a new approach to biomedical prevention is emerging. Antiretroviral chemoprophylaxis (AC) has been demonstrated to be effective by protecting men who have sex with men (MSM) when co-formulated tenofovir-emtricitabine (TDF/FTC) is used orally every day as pre-exposure prophylaxis (PrEP) (iPrEx study) (1); and for at risk South African women when 1% tenofovir vaginal gel is used pericoitally (2). However, in both these landmark studies, the efficacy of AC was significantly attenuated by non-adherence. Since the beginning of the epidemic, MSM have been, and continue to be, one of the largest groups of people at risk for new infections in the U.S. and around the world (3, 4). Thus, for AC to be effective as a public health intervention, culturally tailored programs designed to optimize adherence must be developed. Design: This R34 will adapt and pilot test an intervention to maximize oral AC adherence in MSM, laying the groundwork for a future R01 to test the efficacy of a combined biomedical and behavioral prevention intervention. We propose to: 1) conduct formative, qualitative research to better understand perceptions of AC efficacy, barriers and facilitators of AC use, and to understand contextual variables such as how high-risk MSM would integrate AC into their decision-making regarding partner selection (i.e. use in stable partnerships vs. use with anonymous partners). Accordingly, focus groups will be conducted with MSM who participated in the iPrEx or CDC PrEP study at Fenway Health, and we also will solicit input from our Community Advisory Board and other key MSM stakeholders; 2) use these data to develop and openly pilot a PrEP adherence intervention that can be delivered along with PrEP clinical monitoring for high-risk MSM; and 3) to conduct a pilot randomized controlled trial of this PrEP package compared to an active, time-matched control. The primary outcome will be adherence, as measured by medication event monitoring systems (MEMS) caps, and the secondary outcome will be decreased sexual risk compensation associated with PrEP. Intervention development process: The proposed project follows an iterative approach for intervention development by first conducting formative research, second openly piloting the intervention and refining it, and third, by conducting a pilot RCT. This will lay the groundwork for a full-scale trial to test the optimal methods to administer PrEP and to optimize adherence. Innovation: PrEP is the first biomedical prevention intervention to have been shown to be effective in decreasing HIV in incidence in MSM; but optimal implementation will require concurrent behavioral intervention, as evidenced by the substantial non-adherence associated with HIV incidence in the iPrEx study. The proposed study will allow for the development of an optimal AC prevention package, including combined biomedical and behavioral approaches to HIV prevention.